Lead is a pervasive and potent neurotoxicant that produces persistent, concentration-dependent retinal, visual-motor, auditory and cognitive deficits in man and animals following exposure during development and adulthood. Approximately 2 million young children in the USA have blood [Pb] equal to or >10 mu g/dL, the currently accepted """"""""safe"""""""" level, and millions more have levels of 2.5-10 mu g/dL, which place them at risk for these adverse health effects. Postnatal blood [Pb] equal to or >20 mu g/dL produce SUBNORMAL rod-mediated electroretinograms (ERGs). In contrast, recent results reveal that 7-10 year old children with low-level (blood [Pb] from 4-14 mu g/dL) gestational and continuous postnatal lead exposure have unique SUPERNORMAL rodmediated ERGs characterized by increases in a-wave amplitude, b-wave amplitude and sensitivity. The overall objective of this research is to determine the sites and molecular mechanisms underlying ERG supernormality in children exposed to low-level lead during gestation. We developed a new rat model of lowlevel gestational lead exposure (blood [Pb] of 8-12 mu g/dL) that produces similar persistent supernormal rodmediated ERGs in adult rats. The proposed studies are designed to test the hypothesis that lead exposure during perinatal development produces ERG supernormality by altering the primary mechanism underlying the rod photoreceptor a-wave rod cGMP hydrolysis - and by altering the dopaminergic-modulated input underlying the b-wave amplitude and sensitivity. Specifically, we will determine whether perinatal lead exposure: 1) causes persistent supernormal ERG a- and b-waves by independent changes in rods and inner retinal neurons, respectively, 2) decreases the steady-state rate of rod cGMP hydrolysis by inhibiting the binding of any of the critical transcription factors to the rod cGMP phosphodiesterase beta-subunit promoter, and 3) produces TNF-alpha-mediated apoptotic cell death and dysfunction of dopaminergic retinal neurons resulting from the elevated retinal TNF-alpha levels measured following low-level perinatal lead exposure in rats. The results from these functional (ERG), biochemical, molecular and immunocytochemical studies will: 1) determine the mechanisms underlying the rod-mediated ERG supernormality, 2) establish the critical period of retinal (neural) vulnerability during gestational development and 3) provide essential neurotoxicity data on low-levels of lead exposure that is of increasing scientific and regulatory concern.
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